Discovery of BAY\n2413555, First Selective Positive\nAllosteric Modulator of the M2 Receptor to Restore Cardiac Autonomic\nBalance

Autonomic\ndisbalance, i.e., sympathetic overactivation and parasympathetic\nwithdrawal, is a causal driver of disease progression in heart failure.\nWhile sympatholytic drugs are established treatments, no drug therapy\nrestoring vagal control of cardiac function is available. We report\nhere the HTS-based discovery of a novel class of 1,8-naphthyridin-4(1H)-one\ncarboxamides acting as positive allosteric modulators (PAMs) of the\nM2 muscarinic acetylcholine receptor (M2R). M2R is the main postsynaptic\nmyocyte receptor regulating heart rate, electrical conduction, and\ncontractile strength. Extensive optimization of the screening hit\nin terms of potency, permeation, metabolic stability, and solubility\nultimately resulted in the discovery of the first-in-class clinical\ncandidate BAY 2413555 (<b>27</b>). With an overall technical\nprofile compatible with once-daily oral administration in a phase\n1 study, no apparent effects on blood pressure, and a mechanism that\nlargely preserves autonomic regulatory capacity, BAY 2413555 could\nbe the tool to finally study the restoration of autonomic balance.